No abstract

Rationale Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings we hypothesized that coping styles are influenced by endocannabinoids. Objectives Here we tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e. we studied the impact of URB597 on the two main attributes of coping styles. Methods Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. Results Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail pinch test, i.e. they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions. Conclusions URB597 treatment induced behavioral changes indicative of a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Albeit further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g. anxiety and depression) and in physical diseases where active coping is therapeutically desirable.

14Rationale Recent evidence suggests that in addition to con- scores, which is likely due to a ceiling effect. We hypothesized 32 that stronger stressors would wash out individual differences 33 in coping; therefore, we exposed mice to foot-shocks that 34 decreased locomotion and increased freezing in all mice. 35URB597 ameliorated both responses. The re-exposure of mice 36 to the shock cage 14 days later without delivering shocks or here to evaluate the impact of URB597 in conjunction with the 173 pre-existing phenotype of mice (see "Experimental design"). We instrumented the subjects with EEG and EMG electrodes The recording cable was attached to a low torque commu- Experimental design 265In experiment 1, we studied the effects of URB597 on coping attempts was larger than the duration of resting, confirming that 274 the stressor was mild and did not induce a general inhibition of 275 behavior. Mice were categorized as passive copers if the escape/ 276 resting ratio was smaller than 1.5. In these mice, the duration of 277 escape attempts was larger than the duration of resting by 33 % 278 or less. Mice were assigned to the active coping group if the 279 escape/resting ratio was larger than 3. In these mice, the dura- 304The contextual reminder was administered 14 days after 305 shock exposure. As during the shock day, mice were 306 connected to the recording cables at 7 AM, and baseline sleep 307 patterns were established between 8 and 9 AM. Mice were 308 transferred to the shock-associated Plexiglas boxes at 10 AM. Results 345The effects of URB597 on escape attempts in the back test 346As the duration of resting and escape attempts was mutually 347 exclusive (the other two behaviors being very short; see earlier 348 discussion), only data on escape attempts were shown here. 349URB597 did not affect the duration of escape attempts overall. (Fig. 1a). These findings replicated those obtained in the likely unable to show further increases due to a ceiling effect. 363To control for the impact of baseline behavior, data were 364 reanalyzed by taking coping styles into account. These were the two trials for all three coping styles (p >0.5) (Fig. 1c). In (Fig. 1d) (Fig. 2b) (Fig. 2c). Interestingly, the direction of explora- (Fig. 2d). Exploration directed towards the air 412 ("upward search") was not affected (data not shown). 413Taken together, these findings show that electric shocks 414 markedly reduced behavioral activity, and URB597 amelio- Fig. 3a). At the end of the investigation period, control mice 436 slept significantly more after the reminder than after the shock, The period of fragmented sleep covered the whole post-shock 444 period albeit its magnitude was gradually reduced (Table 2). (Table 2; Fig. 3d). 454Taken together, the findings suggest that the URB597- 455induced increase in active coping with shocks had a long- 456term emotional impact as shown by the sleep patterns. 457Freezing during the contextual reminder and correlations 458Mice readily showed freezing when...

N-methyl-D-asparate (NMDA)-mediated glutamatergic neurotransmission is strongly involved in the development of trauma-induced behavioral dysfunctions, and indirect evidence suggests that NR2B subunit-expressing NMDA receptors are primarily involved in this process. Earlier studies showed that NR2B blockers inhibit the acquisition of conditioned fear, a frequently used model of post-traumatic stress disorder, but their effects on the expression of conditioned fear was poorly studied. We investigated here the effects of the selective serotonin reuptake blocker, fluoxetine, the NMDA blocker, MK-801, and the NR2B subunit blocker, Ro25-6981 on the expression of conditioned fear. Rats received 10 foot shocks administered over 5 min and were tested 24 h later in the shocking context. Treatments were administered 1 h before testing. Shocks dramatically increased freezing and reduced exploration. MK-801 and Ro25-6981 significantly ameliorated both changes. The effects of fluoxetine were less pronounced. In the open field, MK-801 increased locomotion, ataxia, and stereotypy (effects typical of NMDA blockade). Neither fluoxetine nor Ro25-6981 affected locomotion in the open field. Thus, the NR2B-specific NMDA blockade preserved the beneficial effects of general NMDA antagonists on the expression of conditioned fear but did not produce the locomotor side-effects typical of the latter. These findings warrant further studies on the effects of NR2B antagonists in models of post-traumatic stress disorder.